Our overall goals involve a comprehensive approach to both the intra- and extra-renal consequences of advancing chronic renal failure. The studies will emphasize the nature of the adaptations in nephron function that occur in the transition from health to end-stage chronic renal disease and will be so oriented as to examine as carefully as possible the biologic control systems that participate in the functional adaptations for a series of specific solutes. Among these control systems, continuing interest and attention will be directed to the sodium (or volume) control system. Efforts, initiated aproximately a decade ago, to isolate a natriuretic hormone which we believe to be a key modulator of sodium excretion have moved forward in a very substantive way within the last year and we feel that the goal is now within reach. A number of studies also will be performed in an effort to characterize the "detector" limb of the sodium control system. A detailed, longitudinal study will be undertaken on a number of aspects of the calcium-phosphorus-vitamin D-parathyroid hormone axis in chronic progressive renal disease. These studies have the unusual character of being designed in concert by two groups of investigators representing different schools of thought. The protocols are the product of numerous and detailed discussions. The concept that at least certain of the adaptations in nephron function may be mediated by "messenger" hormones and that when the levels of these hormones in the blood become high enough "trade-off" abnormalities may ensue will be further explored. Particular emphasis will be placed on the role of PTH and of the still putative natriuretic hormone as potential uremic toxins. Finally, a number of questions relating both to the intrinsic changes in function of the nephron in chronic disease and to its responsivity to extra-renal mediators of tubular transport will be examined using isolated perfused tubules or segments from normal rabbits and rabbits with chronic renal disease.